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Could this exciting molecule hold to key to cure for ALS?

By Dr Theron Hutton MD

ALS is perhaps one of the scariest diagnoses a person could face. First recognized in the late 1800s and also known as Lou Gehrig's disease ALS has devastated the lives of untold thousands of people by cutting their lives tragically short.

Sporadic adult disease results from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course (1). Most who are diagnosed expect to live on average a short three years after discovery.

While the exact cause of ALS is not clearly understood there is increasing evidence that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem.

NAD+ is a coenzyme that facilitates redox reactions and is found in all living cells. Potential NAD+ promoters now under study include (but are not limited to) niacin (NA), NAM, NMN, and NR Studies by Xie and Roboon et al. In ALS, NAD+ levels become depleted in the energy-demanding motor neurons as the cells are put under high levels of “oxidative stress”.

Studies suggest that the inhibition of NAD+ consuming enzymes or the supplementation with NAD+ precursors also may be potentially useful in the therapy of ALS (2,3, 4, 5, 6, 7).

Given this growing body of knowledge, we are excited about the possibility of offering therapies that give hope in the face of an otherwise hopeless specter.

1. Obrador, E.; Salvador-Palmer, R.; López-Blanch, R.; Dellinger, R.W.; Estrela, J.M. NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis. Biomedicines2021, 9, 1000.

2. Xie, N.; Zhang, L.; Gao, W.; Huang, C.; Huber, P.E.; Zhou, X.; Li, C.; Shen, G.; Zou, B. NAD+ Metabolism: Pathophysiologic Mechanisms and Therapeutic Potential. Signal. Transduct. Target. Ther. 2020, 5, 227. [Google Scholar] [CrossRef] [PubMed]

3. Roboon, J.; Hattori, T.; Ishii, H.; Takarada-Iemata, M.; Nguyen, D.T.; Heer, C.D.; O’Meally, D.; Brenner, C.; Yamamoto, Y.; Okamoto, H.; et al. Inhibition of CD38 and Supplementation of Nicotinamide Riboside Ameliorate Lipopolysaccharide-Induced Microglial and Astrocytic Neuroinflammation by Increasing NAD. J. Neurochem. 2021, 158, 311–327. [Google Scholar] [CrossRef] [PubMed]

4. Magni, G.; Amici, A.; Emanuelli, M.; Raffaelli, N.; Ruggieri, S. Enzymology of NAD+ Synthesis. Adv. Enzymol. Relat. Areas Mol. Biol. 1999, 73, 135–182, xi. [Google Scholar] [CrossRef]

5. Bogan, K.L.; Brenner, C. Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition. Annu. Rev. Nutr. 2008, 28, 115–130. [Google Scholar] [CrossRef][Green Version]

6. Grozio, A.; Sociali, G.; Sturla, L.; Caffa, I.; Soncini, D.; Salis, A.; Raffaelli, N.; De Flora, A.; Nencioni, A.; Bruzzone, S. CD73 Protein as a Source of Extracellular Precursors for Sustained NAD+ Biosynthesis in FK866-Treated Tumor Cells. J. Biol. Chem. 2013, 288, 25938–25949. [Google Scholar] [CrossRef][Green Version]

7. Braidy, N.; Berg, J.; Clement, J.; Khorshidi, F.; Poljak, A.; Jayasena, T.; Grant, R.; Sachdev, P. Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid. Redox Signal. 2019, 30, 251–294. [Google Scholar] [CrossRef]


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